期刊
JOURNAL OF CELL SCIENCE
卷 122, 期 2, 页码 268-277出版社
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.037127
关键词
Integrins; JAM; Leukocyte; Chemotaxis
类别
资金
- Associazione Italiana per la Ricerca sul Cancro
- Association for International Cancer Research
- European Community [LSHG-CT-2004-503573, NoE MAIN 502935, NoE EVGN 503254]
- Italian Ministry of Health, MIUR [2006058482_002]
- Fondation Leducq Transatlantic Network of Excellence
- Deutsche Forschungsgemeinschaft [RE2885-1/1]
- Friedrich-BaurStiftung
The membrane-associated adhesion molecule JAM-A is required for neutrophil infiltration in inflammatory or ischemic tissues. JAM-A expressed in both endothelial cells and neutrophils has such a role, but the mechanism of action remains elusive. Here we show that JAM-A has a cell-autonomous role in neutrophil chemotaxis both in vivo and in vitro, which is independent of the interaction of neutrophils with endothelial cells. On activated neutrophils, JAM-A concentrates in a polarized fashion at the leading edge and uropod. Surprisingly, a significant amount of this protein is internalized in intracellular endosomal-like vesicles where it codistributes with integrin beta 1. Clustering of beta 1 integrin leads to JAM-A coclustering, whereas clustering of JAM-A does not induce integrin association. Neutrophils derived from JAM-A-null mice are unable to correctly internalize beta 1 integrins upon chemotactic stimuli and this causes impaired uropod retraction and cell motility. Consistently, inhibition of integrin internalization upon treatment with BAPTA-AM induces a comparable phenotype. These data indicate that JAM-A is required for the correct internalization and recycling of integrins during cell migration and might explain why, in its absence, the directional migration of neutrophils towards an inflammatory stimulus is markedly impaired.
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